This document summarizes information presented by Matthew A. Lederman, M.D., FACOG on hereditary cancer syndromes including BRCA carrier status and Lynch syndrome. It discusses fertility preservation options for cancer patients such as egg and embryo freezing. It also addresses reproductive decision making considerations for BRCA mutation carriers regarding fertility, risk-reducing surgeries, and use of preimplantation genetic diagnosis.

1. BRCA Carrier & Lynch Syndrome
Fertility and Family Building Event
Matthew A. Lederman, M.D., FACOG

2. Hereditary Cancer Syndromes
• Majority of women with inherited breast and/or ovarian cancers
carry a deleterious mutation for either BRCA1 or BRCA2.

3. Less Commonly, Cancer is Due to Other
Hereditary Syndromes
- In addition to well-described familial syndromes associated with increased risk of breast
and/or ovarian cancer, other gene mutations that appear to moderately increase cancer risk,
include CHEK2, PALB2, ATM, BRCA1-associated RING domain protein (BARD1) gene , BRCA1
interacting protein C-terminal helicase 1 (BRIP1), Mre11 (MRN) complex, RAD51 paralogs ,
and MUTYH
Hereditary Cancer Syndromes Cancer Risk Hallmarks
Lynch, also known as hereditary
nonpolyposis colon cancer
(HNPCC)
Colon, endometrial, ovarian &
stomach
Gastrointestinal polyps
Li-Fraumeni Brest, sarcomas, brain, leukemia,
& adrenocortical
Peutz-Jeghers Gastrointestinal, breast & ovarian Benign skin lesions &
gastrointestinal polyps
Cowden Breast, endometrial &thyroid
Hereditary diffuse gastric cancer
(HDGC)
Gastric & lobular breast

4. BRCA: Background
• Prevalence of BRCA:
- In an unselected non-Jewish population in the U.S., the chance of having a BRCA
mutation is 1 in 400*.
- In Ashkenazi Jews, approx. 1 in 40 individuals has a BRCA mutation.**
• Patients with a BRCA mutation are at increased risk of breast, ovarian, as well as
other cancers, with an earlier age of onset***.
Lifetime Breast Cancer Risk Lifetime Ovarian Cancer Risk
BRCA 1 55-70% 40-60%
BRCA 2 45-60% 10-20%
General Population 13% 1.4%
*McClain 2005, **Roa 1996, ***Antoniou 2003, Chen 2007, Mavaddat 2013

5. Oncofertility
A delay in childbearing combined with an improvement in cancer survival rates
have resulted in more and more women having not had children at the time of
their cancer diagnosis and requiring fertility preservation.
As a result, “Oncofertility” is now a discipline:
- Interdisciplinary field at the intersection of oncology and reproductive
medicine that expands fertility options for cancer survivors.
- Significant proportion of young women diagnosed with cancer are given
the opportunity to preserve their fertility before undergoing gonadotoxic
treatment.

6. Chemotherapy Can Be Harmful to Ovaries
The degree of damage is dependent on a few factors:
• The most important of these factors is the type of chemotherapy.
- High Risk for inducing ovarian failure:
• Cyclophosphamide (alkylatining agent) often used to treat early stage breast cancer.
• Dose dependent
• Age Dependent
- Older patients who have less ovarian reserve are at highest risk for ovarian failure.
• In reproductive age women with breast cancer treated with chemotherapy more than 50% > 40 y/o
experienced ovarian failure vs 30% in those < 35 y/o.
The loss of ovarian function may be permanent or temporary with temporary
amenorrhea (no menses).
There is no data to suggest that chemotherapy directly damages the uterus.

7. Reproductive Success After Cancer and
Treatments is Substantially Decreased
• Patients who have undergone cancer treatment without fertility preservation
have a substantial decrease in their fertility.
- Childhood Cancer Survivor Studies demonstrate that female survivors
were substantially less likely to have live births compared with their
siblings.
- Among female cancer survivors that did not use fertility preservation,
there appears to be an increase in use of IVF and a significant decrease in
first-time parenthood probability.
• Utility of outcome data in several studies assessing ovarian function
after cancer treatment is often limited and does not tell the entire
story because menses rather than pregnancy is used as an endpoint.
- Menses ≠ ability to conceive.

8. Current Best Approach to Fertility
Preservation is Egg or Embryo Freezing
• Ovarian stimulation for embryo cryopreservation or mature oocyte
cryopreservation (egg freezing) is the current best method to preserve
reproductive potential in women of reproductive age and remains the most
likely strategy to result in a subsequent pregnancy in women diagnosed with
cancer.
- Cryopreservation refers to the cooling of cells and tissues to sub-zero
temperatures in order to stop all biologic activity and preserve them for
future use.

9. BRCA and Risk-Reducing Bilateral Salpingo-
Oophorectomy (BSO)
• Women with a BRCA mutation may consider a prophylactic salpingo-oophorectomy
(excision of fallopian tubes and ovaries) to decrease cancer risk.
• Guidelines recommend risk-reducing bilateral salpingo-oophorectomy (BSO) between
the ages of 35-40, or individualized based on age of onset of ovarian cancer in a family
member and once childbearing is complete.
- Studies show that BSO significantly reduces the risk of ovarian cancer.
- Alternative risk reducing strategy
• Risk reducing salpingectomy followed by delayed oophorectomy.
• Growing evidence that fallopian tube is origin of ovarian cancer.
• However, data on its effects on ovarian cancer risk are lacking.
• Various medical interventions to reduce cancer risk or treat malignancy often elicit
fertility and family-planning concerns among young BRCA mutation carriers.
• Specific recommendations for breast cancer risk management include intensive
screening as well as consideration of hormonal and surgical forms of risk reduction.
- In addition to bilateral mastectomy in premenopausal women, obtaining BSO by
the recommended age may significantly reduce risk of breast cancer.

10. Children of BRCA Mutation Carriers Have a
50% Chance of Inheritance
• Option of IVF with preimplantation genetic diagnosis (PGD) to
prevent transmission to offspring.

11. Does Being a BRCA Carrier Impact Fertility?
• Conflicting studies exist regarding effect of a BRCA mutation on fertility.
• There are multiple studies suggesting BRCA mutation carriers (more BRCA 1
compared to BRCA 2) may have decreased ovarian reserve (lower egg quality
and quantity) compared with women without BRCA mutations, as well as
onset of natural menopause at an earlier age. Some studies have also
implied that BRCA mutation carriers undergoing in vitro fertilization (IVF)
may not do as well compared to non-BRCA carriers.*
• However, some studies failed to demonstrate an association between BRCA
status and fertility.**
*Finch 2013, Wang 2014, Titus 2013, Derks-Smeets 2017; **Collins 2013, Michaelson 2014, Pal 2010, Valentin 2013, Shapira 2015

12. • Circulating AMH is a biomarker of ovarian reserve.
• Findings:
- BRCA1 mutation carriers had a 25% lower AMH concentrations than non-carriers and were
more likely to have AMH concentrations in the lowest quartile for age.

14. • Abstract presented at the ASRM annual conference October 2016
• Findings:
- A trend toward accelerated age-related decline in ovarian reserve and oocyte yield was
demonstrated in BRCA 1 carriers.
- Although patients who carry the BRCA mutation are known to have altered DNA repair
mechanism, their embryos did not demonstrate an increased rate of aneuploidy
(chromosomally abnormal embryos), although the number of patients was small in this
study.

15. What Factors Influence BRCA Carriers’
Decisions on Trying to Conceive?
• BRCA carriers are faced with difficult issues regarding their desire to
conceive:
- Risk-reducing surgery (bilateral salpingo-oophorectomy {BSO}).
• When?
- Potential risk of diminished ovarian reserve.
- Risk for passing on the mutation to their offspring.
• 50% of offspring will be a carrier.
• Other factors that may influence BRCA carriers’ decisions on trying to
conceive:
- Age
- Single vs. married
- Size of family desired

16. I am a BRCA Carrier and Want to Have
Children in The Future, What Are My Options?
• Oocyte cryopreservation (egg freezing).
- Single/Not in a Committed Relationship.
• Considering risk-reducing BSO in near future.
• Diminished ovarian reserve.
- In future, after thaw and fertilize eggs, can biopsy developing embryo and
undergo PGD.
• Embryo cryopreservation (embryo freezing).
- Married/In a Committed Relationship.
• Considering risk reducing BSO in near future prior to competing their family.
• Diminished ovarian reserve.
- Option of PGD.
• Annual monitoring of ovarian reserve (AMH and follicle scan of ovary) given
possible increase risk of diminished ovarian reserve.
• PGD
• No fertility-related treatment or monitoring.

17. What Does an IVF/Egg Freeze Cycle
Involve?
There are several steps in an IVF cycle:
• Ovarian Stimulation and Monitoring
• Egg Retrieval
• Fertilization and Embryo Culture
• Embryo Transfer

18. What Does an IVF/Egg Freeze Cycle
Involve?
Ovarian Stimulation and Monitoring
• A patient undergoing IVF usually takes hormone injections for 8-12 days to increase
the number of eggs. Frequent monitoring (bloodwork and ultrasound) is performed to
follow the ovarian response, allowing medication dosage adjustment.

19. What Does an IVF/Egg Freeze Cycle
Involve?
Egg Retrieval
• Under sedation, a fertility specialist extracts eggs via ultrasound guidance. The egg
retrieval is a minimally invasive procedure that normally takes less than 15 minutes.
- In an egg freeze cycle, the eggs are frozen on the same day.

20. What Does an IVF/Egg Freeze Cycle
Involve?
Fertilization and Embryo Culture
• Embryologists use high-power microscopes to fertilize the eggs with sperm in the
embryology laboratory. The resulting embryos are then cultured in a dish.

21. What Does an IVF/Egg Freeze Cycle
Involve?
Embryo Transfer
• A fertility specialist uses an abdominal ultrasound to guide a small catheter through
the cervix and deposit the embryo(s) in the uterus. This procedure usually does not
involve any sedation and takes only a few minutes.

22. Egg Freezing
• Early results from egg freezing were disappointing:
- Low egg survival, fertilization and pregnancy rates after IVF
with thawed eggs.
- Initial protocols used a slow freeze and rapid thaw.
- Mature eggs are difficult to freeze because of the meiotic
spindle and formation of ice crystals.
• New Protocols
- Modifications in cryoprotectant solutions.
- Vitrification: process of cryopreservation using high initial
concentrations of cryoprotectant and ultra-rapid cooling to
solidify the cell into a glass-like state without the formation of
ice crystals.

23. Vitrification is Superior to Slow Freezing
• Multiple studies demonstrated superior results after vitrification.
- Higher egg survival rate.
- Higher fertilization rate.
- Higher top-quality embryos and cleavage rate.
- Greater clinical pregnancy rate per thawed/warmed egg.
• Vitrified eggs have success rates comparable to fresh eggs.
- Comparable fertilization rates, embryogenesis and pregnancy between vitrified eggs
and fresh eggs.
• In fact, in 2012 ASRM revised their committee opinion and stated that this is no
longer experimental and currently vitrification is the preferred method of
cryopreservation. From the published ARSM opinion:
- Good evidence that fertilization and pregnancy rates are similar to IVF/ICSI with fresh
eggs.
- No increase in chromosomal abnormalities, birth defects or developmental deficits in
the offspring.
- Evidence indicates that oocyte vitrification (egg freezing) and warming should no
longer be considered experimental.

24. How Many Eggs Do I Need?
• A frequent question when discussing egg freezing with patients is the number of eggs
required to maximize their chances of success in the future.
- Everyone is so different that there is a wide range based on one’s egg quality.
- Best approach is based on chronologic age and chromosomal content.
• How many eggs does it take to make a baby?
- 1 egg ≠ baby
• Ideal number varies based on the patient’s age, desired family size and finances.
- No right or wrong answer
- 10-20 mature eggs is typically the goal
- Recent abstract by Goldman presented at ASRM 2015 looked at the number of mature eggs
to achieve a live birth.
• < 35: 8 eggs
• 35-37: 10 eggs
• 38-40: 14 eggs

25. PGD
• Preimplantation genetic diagnosis (PGD) is the diagnosis of a genetic condition prior
to achievement of a pregnancy.
- Identifies embryos that are predicted to be affected with a genetic disease and those that
are not, therefore allowing couples to prevent a pregnancy with a genetic condition.
- PGD is the only way to determine whether an embryo is predicted to be affected with a
genetic condition prior to achieving pregnancy.
• Requires blood work from the patient and the partner in order to create a “DNA
probe” for the specific genetic mutation.
- Depending on the genetic disorder, a buccal (cheek) swab from other family members (i.e.
parents) may also be requested.
- Usually takes 4-8 weeks to create the specific probe.
• An IVF cycle involving PGD includes the process of fertilization of the egg, culture of
the embryo to the blastocyst stage, embryo biopsy, embryo freezing by vitrification,
and DNA analysis to determine if the embryo carries the mutation for the specific
disease (such as BRCA).

26. Aneuploid Screening and PGD
• Aneuploid screening allows for assessment of chromosomal abnormalities in
the embryo (i.e. down syndrome, turner syndrome, trisomies, etc.).
- Aneuploidy (a chromosomally abnormal embryo) is the leading cause of implantation failure
and miscarriage after IVF.*
- Aneuploidy increases with increasing maternal age which is why older women have lower
pregnancy rates and higher miscarriage rates in an IVF cycle.
• In almost all PGD cycles, embryos also undergo aneuploidy screening (known
as PGS, preimplantation genetic screening, or CCS, comprehensive
chromosomal screening, or PGT, preimplantation genetic testing ).
• This process allows identification of the single healthiest and unaffected
BRCA negative euploid (chromosomally normal) embryo.
- These embryos are later thawed and transferred in a frozen embryo transfer cycle (FET).
• Excess euploid and unaffected BRCA negative embryos can be saved for
future attempts at pregnancy, since these embryos can remain frozen
indefinitely.
*Scott 2012, Nasseri 1999, Wener 2012

27. Embryo Biopsy at the Blastocyst Stage

28. • The purpose of this study was to assess the informational needs of BRCA mutation
carriers regarding issues of fertility and preimplantation genetic diagnosis options.
• 13 women participated in a focus group at the 2009 Facing Our Risk of Cancer
Empowered (FORCE) national conference.
- Eligible participants included:
• Carrier for BRCA mutation.
• Strong family history of breast or ovarian cancer.
• Personal history of breast or ovarian cancer.

29. Findings Highlighted by the Focus Group
• The results of this study highlighted the important psychosocial concerns and
informational needs within this population.
- Explored the informational needs of women who were BRCA carriers regarding
issues of reproduction and views on PGD.
- The study demonstrated that BRCA carriers have “special informational needs
regarding issues of cancer prevention, fertility options, as well as the need for
psychosocial support from health care professionals.”
- Participants believed information about fertility options and PGD was not well
discussed by health care providers.

30. Findings Highlighted by the Focus Group
• Feelings of guilt about transmitting the mutation to future children existed.
• Limited quantity of information about fertility options was disappointing.
• Most felt a sense of responsibility to take advantage of PGD technology but
thought a lack of information about the process and procedures existed.
• The majority agreed that even if PGD and IVF were not pursued, there was an
implied responsibility to at least consider options.
• A strong desire for assistance with decision making.
- “A need for a new era of family health professional and preferred to
receive PGD information in an organized and systematic manner from a
professional devoted to working solely with BRCA mutation carriers.”

31. Recent Abstracts Presented at ASRM
• BRCA MUTATION CARRIERS: A NEW TARGET POPULATION FOR FERTILITY PRESERVATION
CONSULTATION AND TREATMENT (Kim 2013)
- Findings:
• Most women with BRCA mutations were interested in fertility preservation
consultation/treatment if they had not yet completed childbearing at time of screening.
• This well-educated group had limited knowledge about the clinical impact of a risk-
reducing BSO on subsequent fertility, or the benefit of a fertility preservation
consultation with egg/embryo banking before a risk-reducing BSO.
• BRCA-positive women tended to report difficulties in conceiving.
• Targeted referrals for fertility preservation consultation at the time of BRCA screening
may help women improve knowledge and allow improved decision-making about
reproductive options.
• REPRODUCTIVE DECISION-MAKING IN PATIENTS DIAGNOSED WITH BRCA MUTATIONS (Chan
2015)
- Findings:
• The knowledge of BRCA carrier status impacts behaviors regarding marriage and
childbearing and the majority of BRCA carriers believe that PGD and prenatal diagnosis
should be offered.
• BRCA carriers desire and would benefit from reproductive counseling after being
informed of their carrier status.

32. Informational Needs Exist for BRCA Carriers
Regarding Issues Related to Reproduction
• Despite our understanding of the medical implications of a BRCA mutation,
there is limited data on how knowledge of carrier status influences decisions
about reproduction and parenthood.
• BRCA carriers may benefit from reproductive counseling after being informed
of their carrier status and therefore improve knowledge and allow improved
decision-making about reproductive options.

33. Is Infertility Treatment Safe for BRCA
Carriers?

34. Is Infertility Treatment Safe for BRCA
Carriers?
• Information for women at an increased risk of developing ovarian cancer due
to BRCA is limited.
- One study of Jewish Israelis evaluated such an association and the investigators reported no
significant relationship between fertility treatment and the risk of BRCA-associated ovarian
cancer.*
• Among women in the general population, collective evidence suggests no
significant relationship between IVF treatment and subsequent risk of
ovarian cancer**.
*Perri 2015; **Rizzuto 2013, Siristatidis 2013, Diergaarde 2014

35. Study Conclusion
• Their findings suggest treatment for infertility does not significantly increase
the risk of ovarian cancer among women with a BRCA mutation.
- However their study was limited by the small number of women who underwent
IVF or used fertility medications, as well as the use of self-reported information.
- Prospective studies with longer follow-up and detailed information on dosage,
type of medication and duration will further clarify the role of infertility treatment
in women at risk for ovarian cancer.
• In an earlier study, these same investigators similarly reported no harmful
effect of fertility medication on BRCA-associated breast cancer*
*Kotsopoulos 2008

36. Ovarian stimulation with concurrent use of aromatase inhibitors
(Letrozole) provides a safe fertility preservation option for women
with breast cancer, including BRCA carriers.

37. Options For Women With a BRCA Mutation Who Plan
on Utilizing PGD at Some Point in the Future and
Families Are Not Yet Complete
Ovarian
Reserve
Diminished
ovarian reserve
Single
Egg Freezing
Married
IVF/PGD/
Embryo banking
Normal
ovarian reserve
Single
Egg freezing
If Age <35
Annual
monitoring of ovarian
reserve
Married
IVF/PGD/
Embryo banking
If Age <35
Annual
monitoring of
ovarian reserve

38. Options For Women With a BRCA Mutation Who Do Not
Plan on Utilizing PGD and Families Are Not Yet
Complete
Ovarian Reserve
Diminished
ovarian reserve
Single
Egg Freezing
If Age <35
Annual
monitoring of ovarian
reserve
Married
IVF/Embryo
banking
If Age <35
Annual
monitoring of ovarian
reserve
Try to conceive
Normal
ovarian reserve
Single
Egg freezing
If Age <35
Annual
monitoring of ovarian
reserve
Married
IVF/Embryo
banking
If Age <35
Annual monitoring of
ovarian reserve
Try to conceive

39. Scenarios
• I am a 30 year old BRCA carrier who is single and in the future I would like to prevent
passing on this mutation, what can I do now?
- She can freeze her eggs now. In the future she can thaw her eggs, fertilize them, and then
undergo PGD.
• I am a 33 year old BRCA carrier who is married. We would like to have 2 kids in the
future, but we’re not ready right now- maybe in 2 more years. We would also like to
prevent passing on this mutation, what can we do?
- The couple can freeze embryos now after undergoing PGD (most patients also elect for
aneuploidy screening at the same time). When the couple is ready to start their family, they
can undergo a frozen embryo transfer of a single embryo that is unaffected and
chromosomally normal.

40. Scenarios
• I am a 39 year old, recently diagnosed BRCA carrier who is single and plan on
undergoing a risk-reducing BSO in the near future. I would like to have kids in the
future. What are my options?
- She can freeze her eggs now prior to a risk-reducing BSO.
• I am a 37 year old, recently diagnosed BRCA carrier who just got married. I would like
to undergo a risk-reducing BSO soon but ideally would like to have 2 kids. What are
my options?
- The couple can freeze embryos now prior to a risk-reducing BSO an also have the option of
undergoing PGD if interested. When the couple is ready to start their family, they can
undergo a frozen embryo transfer cycle.

42. Summary
• Despite our understanding of the medical implications of a BRCA mutation, there is
limited data on how knowledge of carrier status influences decisions about
reproduction and parenthood.
• Women at risk for development of cancer need health care professionals to discuss
not only the medical implications of their carrier status or risk-reducing options, but
also information regarding fertility preservation and PGD.
• BRCA carriers may benefit from reproductive counseling after being informed of their
carrier status and therefore improve their knowledge and allow improved decision-
making about reproductive options.
• No ‘one-size-fits-all’ treatment option exists.